mTORC1 Modulators with Altered Ternary Complex Affinity
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Solution Overview
Problem
Rapamycin, despite its therapeutic potential for chronic diseases, is limited by its adverse safety profile, including side effects such as peripheral edema, hypercholesterolemia, and impaired insulin sensitivity, necessitating the development of alternative compounds that can effectively target the mTOR pathway without these drawbacks.
Innovation Solution
Development of specific compounds represented by Formulas (IA) to (III-H) or their salts, which exhibit altered binding affinities to FKBP proteins and the FRB domain of mTOR, potentially offering similar therapeutic benefits to rapamycin with reduced adverse effects by selectively inhibiting the mTOR pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If rapamycin is used to inhibit mTOR signaling for therapeutic benefit, then lifespan extension and treatment of chronic diseases are achieved, but adverse safety effects such as peripheral edema, hypercholesterolemia, and impaired insulin sensitivity occur
Solution Approach 1:
The patent segments the mTOR inhibition function by developing analogs that selectively target specific aspects of mTOR signaling or specific tissues, rather than using broad-spectrum inhibition. This allows therapeutic benefits to be achieved while minimizing off-target adverse effects through selective action on particular mTOR pathways or cellular compartments.
Solution Approach 2:
The patent applies local quality by designing compounds with modified chemical structures (Formula I analogs) that exhibit differential binding affinity to FKBP12 and tissue-specific mTOR isoforms. This enables the drug to exert therapeutic effects in target tissues while sparing other organs from adverse effects, creating localized action patterns that improve the therapeutic index.
2Duration of action of stationary object
If rapamycin is administered for chronic treatment, then treatment of chronic diseases is achieved, but the prohibitive safety profile limits its use
Solution Approach 1:
The patent changes key molecular parameters by modifying the chemical structure of rapamycin analogs (Formula I compounds) to alter their binding kinetics and metabolic stability. These parameter changes enable prolonged therapeutic action with reduced accumulation and lower incidence of chronic adverse effects, making long-term treatment feasible.
3Adaptability or versatility
If compounds with altered binding affinities to FKBP proteins are developed, then selective mTOR pathway inhibition is achieved, but compound complexity increases
Solution Approach 1:
The patent applies local quality by introducing specific substituent patterns at defined positions on the macrocyclic ring (Formula I structures). These localized structural modifications confer selective binding to FKBP12 and mTOR while maintaining overall molecular simplicity, avoiding the need for complex multi-domain structures.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These compounds demonstrate potent binding to FKBP proteins and altered ternary complex formation with mTOR, potentially providing effective treatment options for mTORopathy with a safer pharmacological profile compared to rapamycin.
Implementation Method 1
these compounds display similar direct binding properties, e.g. similar or improved FKB binding, relative to rapamycin and related compounds
Implementation Method 2
display altered ternary binding affinity, e.g. diminished binding affinity to the FRB domain of mTOR
Data Source
AI summary
The disclosure provides compounds and salts that show high selectivity and inhibitory activity for mTORC1 and uses thereof for the treatment of disease.